Amino esters of diaryl succinic acids



I metrical diaryl-succinic Patented Nov. 5, 1946 r Karl G. Pleger,

Hill, New Haven, Conn Cyanamid Company,

poration of Maine Rochester, N. Y., and Arthur J. assignors to American New York, N. Y., a core No Drawing. Application March 31, 1942,

- Serial No. 436,959

, Claims. (crate- 475) 1 This case relates to the 'alkamine esters of symacids.

Many different compounds have been synthesized in the course of a long search for a local anesthetic which would be a satisfactory substitute for cocaine. Although cocaine is the the usefulness of its estersas an anti-spasmodic standard against which local anesthetics are usually compared, it has many undesirable properties. Notable among these are its high tox- "icity and narcotic character, because of which its clinical use has practically disappeared. De-

spite the large amount of work which has been carried out inattempts to find a suitable substitute, the list of effective and non-toxic compounds suitable for clinical use remains sur'prisingly small, not more than about half a dozen having gained any wide acceptance. There still remains a real demand for a compound which is highly active as a local anesthetic and which is at the same time free from irritating, toxic and narcotic properties.

Most of the satisfactory local anesthetics are alkamine esters of various acids although the particular properties of any alkamine ester de-. pend upon the particular aminoalcohol and particular acid from which it is made. For example, in the past it has been believed that the alkamine esters derived from acids containing an aromatic group were most effective as local anesthetics, followed in descending order of activity by alkamine esters of acids containing groups such as pyrrol, thiophene, furan and alkyl. Accordingly, for example, the hydrochloride 'of the p-diethylaminoethyl ester of p-aminobenzoic acid has been widely used although it is not particularly satisfactory as a surface anesthetic nor of particularly satisfactory duration as a nerve block. It has been found,

substitution in the acid from which the ester is derived. Not only do these various substitutions afiect the general properties but specifically afiect the usefulness of the alkamine esters for various purposes. Varying the substituents of the acid afiects'the relative anesthetic activity of esters derived from it with a designated aminoalcohol, both as a surface anesthetic and as a nerve block. Varying the substituents oi the'acid also affects however, that the properties can be varied almost at will by proper and as a mydriatic.

The present invention with alkamine esters ofstituted succinic acids by the following formula:

is particularly concerned symmetrical diaryl-subin which Ar represents an aryl radical and E represents an alkamine radical. Ar may be a substituted or unsubstituted aryl radical such as phenyl, tolyl, aminotolyl, anisyl, naphthyl, ethoxynaphthyl and the like.

E preferably represents an alkamine radical of the type formula:

- R: -niN RI in which R1 represents a hydrocarbon residue such as that of an alkyl radical and Re and Rh represent the same or different radicals or R2 and .Rs may represent hydrocarbon residues which with the N go to make up a heterocyclic ring such as that of'piperidine or morpholine. Typical examples of the aminoalcohols of the type concerned in'the present application are: p-diethylaminoethanol, 'y-diethylaminopropanol, p-dipropylaminoethanol, .p-dibutylaminoethanol, t-dipropylaminobutanol, 3-N,N-ethylcyclohexylaminoethanol, 6-dibutylaminobutanol, p-N,N-phenylethylaminoethanol, 4-diethylaminocyclohexanol, p-4-morpholinoethanol, 3-5-dimethyl p 4-morpho1inoethanol, p-piperidinoethanol and the like.

Typical of the acids, with the alkamine esters of which the present invention is particularly concerned is diphenyl-succinic acid. In the following disous'sion and examples thisacid will be used to illustrate the invention. However, it is intended to be merely illustrative and not to limit the invention to this particular acid.

Symmetrical 'diphenyl-succinio acid may be readily prepared in the form of its ethyl ester by treating the ethyl ester of phenyl acetic acid which may be represented be readily prepared.

. tion of the in an ether solution with iodine and sodium ethoxide. The action is readily carried out and the ester occurs as both the meso and racemic forms. Separation of the two may be easily made by means of their different solubilities. Either form upon saponification in alcoholic caustic solution of sodium or potassium hydroxide gives a mixture of meso and racemic diphenyl-succinic acid. If desired the two acid forms may be separated by the difference in the solubility of their alkaline earth metal salts.

Since any attempt to form an acid chloride in the usual manner, as with thionyl chloride, of the dipheriyl-succinic acid, some form of alcoholysis is necessary as a means of forming the alkamine esters. If an alcoholysis is carried out, the products are all in the same form whether the mesa or the racemic form is used as a starting material. Since the alkamine esters are the products which aredesired there is, therefore, little practical advantage in separating either the two forms of ester or thetwo forms of the acid.

Direct esterification is highly impractical because of the low reaction rates and poor yields.

by treatment of the acid produces anhydrization Our preferred procedure is to form a simple alkyl ester and then to carryout a catalyzed ester interchange, preferably removing the replaced alcohol as fast as it is liberated. according to the processset forth in the Hill and Holmes application Serial No. 431,822, filed Eor this process the mixture of meso and racemic ethyl esters of diphenyl-succinic acid produced as set forth above terial.

The alkamine ester bases are usually clear, somewhat amber colored oils which distill at fairly high temperatures even under reduced pressure. They are usually soluble in alcohol, acetone and ether and usually insoluble in water. These alkamine esters are slightly basic in reaction and may be readily converted into salts such as the hydrochloride, nitrate, sulfate, hydrobromide, phosphate, tartrate, citrate andthe like. The hydrochlorides are probably the easiest to prepare and are usually preferable because of this fact.

The hydrochlorides, for example, are generally white crystalline solids having a sharp melting point and being in general very soluble in water, alcohol, acetone, chloroform and benzene. The hydrochloric acid salts of the base in aqueous solution exhibit high activity and low toxicity as surface anesthetics.

If so desired the quaternary compounds such as the methiodide, ethobromide and the like may The quaternary compounds have a certain advantage in that they are usually more readily crystallized than are some of the hydrochlorides of high melting point which are is an excellent starting malikely to;be extremely hygroscopic, The quaternary compounds may be readily prepared by treating the base compound such as'methyl or ethyl bromide and the salts may be precipitatedby removing, a. poralcohol and adding ether to the residue until precipitation stops. The quaternary compounds have sharp melting points when purifled by recrystallization from a suitabl solvent such as an acetone-ether mixture.

The present invention will be more fully illus- February 21, 1942..

in an alcoholic solution with a trated in connection with the following examples which are illustrative and not by wayof limitation. All parts are by weight unless otherwise noted.

boiled at 225-230 0. (5 mm.).

Exam: 1 Ethyl-sym-diphenyl succinate OCHCOOClH! Olnooocna,

Dry pulverized sodium ethylate fr om 11.4 parts of sodium was suspended in parts of dry ether in a one liter three neck flask supplied with condenser, stirrer and dropping funnel. To this suspension was added 70 parts of phenyl acetic ester and then over a period of one hour, during stirring and cooling, a solution of 54.6 parts of iodine in 280 parts of dry ether. The reaction mixture became turbid from formation of an insoluble white precipitate. The mixture was finally stirred for two hours at room temperature. Water and sodium thiosulphate were then added. The white precipitate, now suspended in the water layer was filtered off and crystallized from 95% alcohol. A pure white crystalline solid melting at mil-141 C. was obtained. This is the ,B- or meso ester. The ether layer of the filtrate was then separated, dried over sodium sulfate, the ether distilled off and the residue recrystallized from alcohol. The resulting product was washed with ether which dissolved the aor racemic ester leaving. the meso Y, ester. To recover the racemic ester, the ether was evaporated from the filtrate and the residue recrystallized from petroleum ether. The ester thus obtained melted at 80-82 C.

EXAMPLE 2 Di-(p-diethylaminoethyl) -sym-diphenyl succinate Oonoooomcnmonsm Olmooo omcmNwium To a solution of 0.2 part of sodium in 32- parts of p-diethylaminoethanol was added 26 meso-diphenyl-succinic ester. The mixture was then heated by means of an oil bath at Mil- C. for 44 hours. After completion of the reaction, the excess p-diethylaminoethanol was distilled off and the residue shaken with a mixture of dilute hydrochloric acid and ether until solution was complete. The hydrochloric acid layer was separated, washed twice with fresh portions of ether and then treated with potassium carbonate until a sludge formed. The sludge was then extracted with ether until removal of the aminoester was complete. The ether solution of the base was dried over sodium sulfate, the solution filtered, the ether distilled off and the residue vacuum distilled. After-a few drops of foreruns an amber colored liquid distilled at 220-235 C. (5 mm.)

EXAMPLE 3 Di- (p-diethylaminoethyl) -sym-driphenyl succinate The procedure of Example 2 was followed in an experiment using the racemic dlphenyl-succinic ester. In this case, the amber colored product parts of Exzmru 4 Hydrochloride of di-(p-diethylaminoethyl) -symdiphenyl succinate @cncooomommotmhnm I C l11ooocmo1zmwmmne A portion of the aminoester obtained by the alcoholysis of meso-diphenyl-succinic ester with fi-diethylaminoethanol was dissolved in dry ether and treated with dry hydrogen chloride until no more precipitate formed. The ether was then decanted and the gummy precipitate shaken with another portion of dry ether which was in turn decanted. Dry acetone was added to the hydrochloride. Part of the hydrochloride dissolved, and part assumed the form of a flocculent precipitate. After standing in a refrigerator overnight, the precipitate was filtered off, washed with acetone and dry ether and then dried ina vacuum desiccator overnight. The hydrochloride was awhite, friable, non-hygroscopic amorphous powder which melted at 188-190 C. The salt was soluble in water and alcohol but insoluble in acetone and ether.

EXAMPLE 5 Hydrochloride of di-(s-diethyzammoethyz) -symdiphenz/l saccinate EXAMPLE ni-( -diethylam-inopromll) -sym-dii henyl succinate @cncobomomommomm Ollie o CH:CH:CH2N(C:H5):

To a solution of 0.2 part of sodium in 25 parts of -diethylaminopropanol was added 12 parts of meso-diphenyl-succinic ester. The mixture was heated by means of an oil bath at 140-155 C. for 55 hours. The excess 'Y diethylaminopropanol was then distilled off under reduced pressure and the residue shaken with a. mixture of dilute hydrochloric acid and ether until solution was effected. The hydrochloric acid layer was separated, washed twice with fresh portions of ether and then treated with potassium carbonate until a sludge formed. The sludge was then extracted four times with ether to remove the free aminoester. The ether solution of the base was dried over sodium sulfate, filtered, the ether distilled off and the residue vacuum distilled. After a few drops of foreruns a reddish brown liquid distilled at 230-250 C. (5 mm.).

Dt-(v-diethyldminopropyl) -sym-diphen11l succinate @cncooomomoamwmm Olnccoomomommomm In an experiment using the procedure of Example 6 racemic-diphenyl-succinic ester was alcoholized by means of a solution of sodium in 'Y-diethylaminopropyl alcohol. In this case the temperature was kept at 1,45-l55 C. for 44 hours.

15 Subsequent treatment of the reaction product was thesame as in the preceding experiment.

The reddish brown product boiled at 235-255 C. (5 mm.).

Hydrochloride of di (Y diethylammopropyl) sym-diphenyl succinate alcoholysis of meso-diphenyl-suc'cinic ester with 'v-diethylaminopropanol was dissolved in dry ether and treated with dry hydrogen chloride until precipitation was complete. The ether was then decanted and the gummy precipitate shaken with another portion of dryether which was also decanted. Dry acetone was added to the hydrochloride. After it had been shaken, the salt assumed the form of a fiocculent precipitate but would not dissolve to any considerable extent. A small amount of ether was added to the mixture which was then allowed to stand in a refrigerator overnight. The solid was filtered off, washed with acetone and ether and dried in a vacuum desiccator. ,The hydrochloride was white, dry and friable and melted at 165-170 C. Although soluble in water and alcohol, the salt was insoluble in'acetone and ether.

EXAMPLE 9 Hydrochloride of di (Y diethyldminopropyl) 50 symdiphenyl saccinate @0110 0 o onlonlommcinornoi Gino OOCHrOH2CHzN(G;Hs)2.HCl

A portion of the aminoester obtained bythe alcoholy'sis of racemic diphen'yl succinic ester with 'v-diethylaminopropanol was subjected to the treatment of Example 8. The same observations were noted. The final product had the same appearance, melting point and solubilities as the hydrochloride obtained in Example 8.

. EXAMPLE 10 .Di-(p-di-n-butylaminoethyl) -sym-diphenyl succinate @0110 oocnzommcrum @Jmc o ocmcmmcinoz Y A portion of the aminoester obtained by the the residue shaken with a mixture of dilute hydrochloric acid and ether. An oily third layer formed between the acid and ether layers. The

two layers were extracted twice with ether to remove any diphenyl-succinic ester. The two layers were then combined and treated with potasslum carbonate until a sludge formed. The tree aminoester was separated from the sludge by means of several ether extractions. The "ether extracts were dried over sodium sulfate, the solu-.

tion filtered, the ether distilled oil and the residue vacuum distilled. After a few drops of foreruns, the aminoester distilled over at 230-250 C. (5 mm.) as a brownish oil.

EXAMPLE l1 Hydrochloride of di-(p-di-n-butylaiminoethgl)- sym-diphenyl succmate Owmoooomdmmcmhncx Ooncooomonmwaimncl A portion of the di-(p-di-n-butylaminoethyl) sym-diphenyl succinate was dissolved in dry ether and treated with dry hydrogen chloride until precipitation was complete. After the reaction mixture had been shaken the ether was decanted from the oil, fresh dry ether added, the mixture again shaken and then allowed to stand in a refrigerator overnight. The ether was decanted and the oily hydrochloride treated with dry acetone. After it had been shaken for a few moments a considerable portion of the hydrochloride solidified while the remainder dissolved. The solid was filtered oil, washed with dry acetone and ether and, dried in a, vacuum desiccator.

The resulting hydrochloride was a white, friable,

amorphous powder which melted at 158-160 C. It was fairly soluble in water and alcohol but insoluble in acetone and ether.

Di- (v-di-n-butylamin0pr mll) -sym-diphenyl succinate @0110 ooomomommoaim Olncooomomcnmmmn To a solution of 0.2 part of sodium in 26 parts of 'y-di-n-butylaminopropanol was added 10 parts of meso-diphenyl-succinicester. The mixture from the sludge by means of several ether extractions. The ether extracts were dried over sodium sulfate, the solution filtered, the ether After the excess 'y-dibutylamino Emu: 13

Hydrochloride of diw-di-n-butylaminopmpullsym-diphem Z succinate A portion of the di-(v-di-n-but laminopropyl) diphenyl suceinate was dissolved i dry ether and treated with dry hydrogen chloride until precipitation was complete. The ether was decanted, the hydrochloride vigorously shaken with another portion of dry etherto remove any adherent hydrogen chloride and this other in turn poured ofi. Dry acetone caused part of the oil to solidify and dissolved the remainder. Afterstanding in a refrigerator overnight, the mixture was filtered, the solid washed with acetone and ether and thendried in a vacuum desiccator overnight. The final product was a white amorphous powder which melted at 171-1'73 C. The hydrochloride dissolved in alcohol and hot acetone but gave asomewhat turbid water solution.

Several of the alkamine esters, notably the di- (p-diethylaminoethyl) diphenyl sucoinate, the di- (q-diethylaminopropyl) diphenyl succinate, and the di- ('y-dibutylaminopropyl) diphenyl succinate in the form of their hydrochloride salts in aqueous solution are particularly useful as local anesthetics. The di- ('y-diethylaminopropyl) diphenyl succinate, for example, as a surface anesthetic is but slightly less active than cocaine, produces anesthesia for three times the duration of cocaine and is only about 1 5 as toxic. Similarly as a nerve block, it is only approximately /3 as toxic and has aduration of about four times that of cocaine. It has the further advantage that when mixed with epinephrine and injected subcutaneously it does not produce a discoloration.

We claim: 1. Di-(p-diethylaminoethyl) diphenylsuccinate. 2'. Di diethylaminopropyl) diphenylsuccinate.

3. Di iq -dibutylaminopropyl) diphenylsuccinate.

' 4. As new compositions of matter, the di-esters v of symetrical dlphenyl succinic acid having the it i N KARL G. PLEGER. ARTHUR J. HILL. 

